bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–06–08
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes.
  2. Clearance of protein aggregates during cell division.
  3. C. elegans SSNA-1 is required for the structural integrity of centrioles and bipolar spindle assembly.
  4. Linear ubiquitination of p31comet by HOIP couples cytokine response with mitotic regulation.
  5. Loss of negative regulation by HDAC1 and REST contributes to MAD1 overexpression in breast cancer.
  6. Protocol for identifying genomic binding sites of mitotic bookmarkers in Drosophila neural stem cells and cultured mammalian cells.
  7. Nitric oxide regulates spindle dynamics to modulate the maturation of goat oocytes.
  8. Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity.
  9. RAS/ERK signaling and PLK1: Coordinating developmental regulation and disease mechanisms.
  1. EMBO J. 2025 Jun 04.
    MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes.
    Shuhei Yoshida, Reiko Nakagawa, Kohei Asai, Tomoya S Kitajima.
      Incorrect kinetochore-microtubule attachment leads to chromosome segregation errors. The risk of incorrect attachment is high in acentrosomal oocytes, where kinetochores are surrounded by randomly oriented microtubules until spindle bipolarization. Regulation of the temporal relationship between acentrosomal spindle bipolarization and kinetochore-microtubule attachment is unknown. Here, we show that in mouse oocytes, MPS1, a kinase more active at kinetochores with less stable microtubule attachment, promotes timely spindle bipolarization before kinetochores stably attach to microtubules. In MPS1-inhibited oocytes, spindle bipolarization is delayed and depends on microtubules stably attached to kinetochores, resulting in incorrect attachments. We propose a two-step kinetochore-based model where unstable and stable attachment states act sequentially for acentrosomal spindle assembly to reduce the risk of egg aneuploidy.
    Keywords:  Kinetochore; Microtubule; Oocyte; Spindle
    DOI:  https://doi.org/10.1038/s44318-025-00461-w
  2. Elife. 2025 Jun 06. pii: RP96675. [Epub ahead of print]13
    Clearance of protein aggregates during cell division.
    Shoukang Du, Yuhan Wang, Bowen Chen, Shuangshuang Xie, Kuan Yoow Chan, David C Hay, Ting Gang Chew.
      Protein aggregates are spatially organized and regulated in cells to prevent the deleterious effects of proteostatic stress. Misfolding of proteins in the endoplasmic reticulum (ER) results in aggregate formation, but how the aggregates are processed, especially during cell division is not well understood. Here, we induced proteostatic stress and protein aggregation using a proteostasis reporter, which is prone to misfolding and aggregation in the ER. Unexpectedly, we detected solid-like protein aggregates deposited mainly in the nucleus and surrounded by the ER membrane. The membrane-bound aggregates were then cleared as cells progressed through mitosis and cytokinesis. Aggregate clearance depended on Hsp70 family chaperones in the ER, particularly BiP, and proteasomal activity. The clearance culminated at mitotic exit and required cyclin-dependent kinase 1 (Cdk1) inactivation but was independent of the anaphase-promoting complex (APC/C). The ER reorganization that is active during mitosis and cytokinesis was required for the aggregate clearance. Thus, dividing cells reorganize the ER networks to allow BiP to clear the protein aggregates to maintain proteostasis in the newly divided cells.
    Keywords:  ER reorganization; aggregates; cell biology; chaperone; human; mitosis; proteostasis
    DOI:  https://doi.org/10.7554/eLife.96675
  3. Nat Commun. 2025 Jun 05. 16(1): 5220
    C. elegans SSNA-1 is required for the structural integrity of centrioles and bipolar spindle assembly.
    Jason A Pfister, Lorenzo Agostini, Lorène Bournonville, Aurélien Perrier, Prabhu Sankaralingam, Zachary G Bell, Virginie Hamel, Paul Guichard, Christian Biertümpfel, Naoko Mizuno, Kevin F O'Connell.
      Centrioles play key roles in mitotic spindle assembly. Once assembled, centrioles exhibit long-term stability, but how stability is achieved and how it is regulated are not completely understood. In this study we show that SSNA-1, the Caenorhabditis elegans ortholog of Sjogren's Syndrome Nuclear Antigen 1, is a constituent of centrioles and centriole satellite-like structures. A deletion of ssna-1 results in the formation of extra centrioles. We show that SSNA-1 genetically interacts with the centriole stability factor SAS-1 and is required post assembly for centriole structural integrity. In SSNA-1's absence, centrioles assemble but fracture leading to extra spindle poles. However, if the efficiency of cartwheel assembly is reduced, the absence of SSNA-1 results in daughter centriole loss and monopolar spindles, indicating that the cartwheel and SSNA-1 cooperate to stabilize centrioles during assembly. Our work thus shows that SSNA-1 contributes to centriole stability during and after assembly, thereby ensuring proper centriole number.
    DOI:  https://doi.org/10.1038/s41467-025-59939-0
  4. Cell Biosci. 2025 Jun 03. 15(1): 75
    Linear ubiquitination of p31comet by HOIP couples cytokine response with mitotic regulation.
    Yifeng Gao, Qing Yin, Yaser Gamallat, Michael G Grant, Aidan H Snell, Xingxing Shi, Lara N Ulstad, Arshita Singh, Tingan Chen, Joseph O Johnson, Dorina Avram, Lixin Wan.
       BACKGROUND: Inflammation and genomic instability are among the hallmarks of human cancer. Proinflammatory cytokines induce DNA damage through the accumulation of reactive oxygen and nitrogen species (RONS), which often leads to base alternations. The link between proinflammatory cytokines and chromosomal instability remains largely elusive.
    RESULTS: Here, we report that the mitotic checkpoint protein p31comet (MAD2L1BP) is modified by linear ubiquitination via the E3 ubiquitin ligase HOIP after cytokine stimulation. HOIP-mediated polyubiquitination of p31comet occurs on its C-terminal lysine residues. Ubiquitinated p31comet displays reduced binding to PLK1, which phosphorylates and inactivates p31comet. Thus HOIP positively  regulates p31comet function. Consistent with this notion, HOIP-deficient cells exhibit prolonged mitotic duration similar to p31comet knockout. Mitotic defects are also more prevalent in cells without HOIP or p31comet. Moreover, compared with the cells expressing wild-type p31comet, cells expressing a ubiquitination-deficient p31comet mutant take more time to complete the M phase.
    CONCLUSIONS: Our results together uncover a mechanistic link between the proinflammatory cytokines and the mitotic checkpoint pathways. This molecular switch could be explored as a potential therapeutic target in inflammation-driving or p31comet overexpressed cancer types.
    Keywords:  Anaphase-promoting complex; CDC20; HOIP; LUBAC; Mitotic checkpoint complex; P31comet ; Proinflammatory cytokine; Spindle assembly checkpoint
    DOI:  https://doi.org/10.1186/s13578-025-01416-8
  5. Mol Biol Cell. 2025 Jun 04. mbcE24120582
    Loss of negative regulation by HDAC1 and REST contributes to MAD1 overexpression in breast cancer.
    Sarah E Copeland, Boya Chen, Avtar Roopra, Beth Weaver.
      Mitotic Arrest Deficient 1 (MAD1), an essential component of the mitotic spindle assembly checkpoint, is commonly overexpressed in breast cancers where it serves as a marker of poor prognosis. MAD1 overexpression is sufficient to permit nontransformed cells to form orthotopic mammary tumors and to promote tumorigenesis in a recently described mouse model with inducible expression of endogenous Mad1. However, the mechanism of MAD1 upregulation in cancer is unclear. Here we report a 440 bp region of the MAD1L1 promoter that confers a repressive phenotype on MAD1L1 transcription. Bioinformatics analysis implicated Histone Deacetylase 1 (HDAC1) in MAD1L1 transcriptional regulation. Consistent with this, HDAC1 localizes to the MAD1L1 promoter and HDAC inhibition increases MAD1 mRNA and protein expression. The MAD1L1 repressive region contains a partial binding site for RE1-Silencing Transcription factor (REST), which utilizes HDAC1 as a cofactor. REST overexpression decreases MAD1 expression. Moreover, breast cancer patient samples show a significant negative correlation between REST and MAD1L1 mRNA expression. These results support a model in which an altered transcriptional program downstream of loss of the tumor suppressor REST, which normally represses MAD1L1 transcription by recruiting HDAC1-containing repressive complexes, contributes to MAD1 overexpression in breast cancer.
    DOI:  https://doi.org/10.1091/mbc.E24-12-0582
  6. STAR Protoc. 2025 May 31. pii: S2666-1667(25)00264-3. [Epub ahead of print]6(2): 103858
    Protocol for identifying genomic binding sites of mitotic bookmarkers in Drosophila neural stem cells and cultured mammalian cells.
    Yuying Shen, Jie Liu, Yan Song.
      Mitotic bookmarkers label key gene loci on highly condensed chromosomes to preserve cell fate memory across mitosis. Here, we present a protocol for identifying binding sites of mitotic bookmarkers (BISMIBs) in developing tissues and cultured cells. We describe a workflow for isolating mitotic and interphase cells from Drosophila larval brains and HEK293T cells independent of cell-cycle synchronization. We further detail procedures for low-input in vivo CUT&Tag (Cleavage Under Targets & Tagmentation) sequencing. This protocol is applicable for identifying binding sites for mitotically retained factors in developing tissues. For complete details on the use and execution of this protocol, please refer to Shen et al.1.
    Keywords:  Cell Biology; Cell culture; Flow Cytometry; Genomics; Model Organisms; Molecular Biology; Neuroscience; Sequence analysis; Sequencing; Single Cell; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.103858
  7. Theriogenology. 2025 May 29. pii: S0093-691X(25)00243-2. [Epub ahead of print]245 117517
    Nitric oxide regulates spindle dynamics to modulate the maturation of goat oocytes.
    Rui Xu, Zhi Zheng, Weizhao Bai, Minghui Liu, Sihai Lu, Sha Peng, Menghao Pan, Baohua Ma.
      Oocyte maturation is a complex and tightly regulated process. Nitric oxide (NO) has been implicated in the regulation of oocyte maturation, but its precise mechanism of action remains unclear. In this study, the inhibition of NO synthase activity using L-NMMA was found to impair meiosis and inhibit the maturation of goat oocytes. Further analysis revealed that the meiotic arrest induced by L-NMMA was primarily due to disruptions in metaphase I (MI) spindle dynamics. Specifically, L-NMMA treatment led to disorganized MI spindle assembly, abnormal chromosome alignment, elevated levels of microtubule acetylation, and sustained activation of the spindle assembly checkpoint. These defects were partially rescued by supplementation with the NO donor sodium nitroprusside (SNP). Proteomic analysis of oocytes from the CON and L-NMMA-treated groups identified a significant downregulation of KIF15 in the L-NMMA group. KIF15 has previously been established as a key regulator of spindle dynamics during oocyte maturation. Moreover, we demonstrated that the RhoA-ROCK signaling pathway modulated KIF15 protein expression in goat oocytes. Our results further showed that reduced NO levels increased RhoA phosphorylation, which in turn suppressed KIF15 expression and disrupted MI spindle dynamics. In conclusion, this study provides new insights into the role of NO in goat oocyte maturation, revealing that it regulates spindle dynamics through the RhoA-ROCK-KIF15 signaling axis.
    Keywords:  Goat; KIF15; Nitric oxide; Oocyte; Spindle dynamic
    DOI:  https://doi.org/10.1016/j.theriogenology.2025.117517
  8. Nucleic Acids Res. 2025 May 22. pii: gkaf449. [Epub ahead of print]53(10):
    Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity.
    Floriane Lagadec, Parmit K Singh, Christina Calmels, Delphine Lapaillerie, Dirk Lindemann, Vincent Parissi, Peter Cherepanov, Alan N Engelman, Paul Lesbats.
      Selection of a suitable chromatin environment during retroviral integration is a tightly regulated process. Most retroviruses, including spumaretroviruses, require mitosis for nuclear entry. However, whether intrinsic chromatin dynamics during mitosis modulates retroviral genome invasion is unknown. Previous work uncovered critical interactions of prototype foamy virus (PFV) Gag with nucleosomes via a highly conserved arginine anchor residue. Yet, the regulation of Gag-chromatin interaction and its functional consequences for spumaretrovirus biology remain obscure. Here, we investigated the kinetics of chromatin binding by Gag during mitosis and proviral integration in synchronized cells. We showed that alteration of Gag affinity for nucleosome binding induced untimely chromatin tethering during mitosis, decreased infectivity, and redistributed viral integration sites to markers associated with late replication timing of chromosomes. Mutant Gag proteins were, moreover, defective in their ability to displace the histone H4 tail from the nucleosome acidic patch of highly condensed chromatin. These data indicate that the chromatin landscape during Gag-nucleosome interactions is important for PFV integration site selection and that spumaretroviruses evolved high-affinity chromatin binding to overcome early mitosis chromatin condensation.
    DOI:  https://doi.org/10.1093/nar/gkaf449
  9. Curr Opin Cell Biol. 2025 Jun 03. pii: S0955-0674(25)00082-1. [Epub ahead of print]95 102544
    RAS/ERK signaling and PLK1: Coordinating developmental regulation and disease mechanisms.
    Han Bit Baek, Swathi Arur.
      The RAS/ERK signaling pathway is a critical regulator of cellular processes such as proliferation, differentiation, and survival, core mechanisms that drive development. Dysregulation of RAS/ERK signaling is implicated in developmental disorders, including RASopathies, as well as in various cancers. Polo-like kinase 1 (PLK1) is a crucial orchestrator of both meiotic and mitotic cell cycle and plays an equally important role in development. Notably, abnormal ERK signaling can produce phenotypes that closely resemble those caused by PLK1 deficiency, suggesting a functional intersection between these pathways. In this review, we explore the emerging links between RAS/ERK and PLK1 signaling during development and highlight the broad range of biological processes potentially governed by their interaction.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102544
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